OVERALL ? Project Summary The vision of the Center for Environmental Genetics (CEG) is to become a global leader in gene-environment interaction (GXE) research and translation. Its mission is to conduct innovative, multidisciplinary GXE research and translate discoveries to disease prevention via community empowerment, at home and around the globe. The Center is a pioneer in GXE research. We have made outstanding progress in the current funding cycle with new initiatives in advancing the understanding of epigenetics as a bridge between genetics and the environment; further defining windows of susceptibility; identifying mechanisms underlying early-origins of complex diseases; and discovering the impact of genetic variants on disease susceptibility. In the coming fund cycle, we will continue on a steep trajectory of progress in mechanism-based GXE knowledge and translation to reduce environment disease. Our optimistic outlook is based on the valuable intellectual and physical Center resources that we have developed over the past 25 years. First, we have built ten highly valued cohorts, conducive to environmental health sciences (EHS) research within the CEG or shared with other NIEHS-EHSC Centers. Second, we have established leading-edge technologies and capabilities in high-throughput multi-omics research. Third, we have some of the most advanced bioinformatics methods and modern pipelines in data analysis to unlock the power of omics for better understanding of the mechanistic basis underlying complex diseases. Finally, we have attracted incredible young talent ready to become the next-generation of EHS leaders through mentoring by a cadre of thought-leaders in the field. Our strength is immense, our resources run deep, and our cohesiveness supports a strong Center identity. Looking to our new funding cycle, we have the following future goals: (1) To expand from regional to international cohorts to further our study of emerging environmental contaminants; (2) To develop novel statistical and bioinformatics methods to identify the individual and cumulative effects of exposures and the interactions of chemicals in a mixture; (3) To extend our omics platform to single-cell transcriptome with epigenome analyses, interrogation of the mitochondrial genome and epigenome and applications of metagenomics to microbiome; (4) To realize the potential of GXE research towards precision medicine-based risk assessment, prevention, and therapies; (5) To minimize environmental disease and promote healthier living in clean environments through partnerships with communities, health care professionals, and policy-makers and to sharpen our focus on vulnerable populations with significant health disparities. Our goals are well-aligned with the eleven goals of the NIEHS Strategic Plan. We believe we again will significantly contribute to the EHS base of knowledge with new concepts and technologies, and develop human capital through training. Our efforts will minimize the impact of environmental exposures on health in Greater Cincinnati, in our nation and across the globe.